1. Field of the Invention
This invention relates to gas dispensers and methods for delivering carbon dioxide (CO2), or other gas to individuals. Similar methods and devices are described in U.S. patent application Ser. No. 09/614,389 filed Jul. 12, 2000, which is incorporated by reference herein. That application describes use of CO2, or other therapeutic gas or agents, and associated transmucosal dispensing apparatus for providing controlled amounts of gas to the nose, mouth and/or eye for use in the relief of headaches, allergic rhinitis and asthma, among other ailments. The present invention, however, includes methods and transmucosal or inhalational dispensing apparatus for co-application of selected drugs with gas and/or vapor to potentiate (i.e., beneficially improve) the action of the drug or of the gas or vapor.
One possible physiological basis for the invention is as follows:
Drugs act upon blood vessels (vasoactive drugs), muscles (myoactive drugs), and/or nerves (neuroactive drugs) to produce their beneficial effects. It is well established that vasoactive drugs (causing vasodilation or vasoconstriction) may be used to relieve allergic rhinitis (e.g., vasocontrictor decongestants) as well as migraine and other forms of headache (e.g., vasoconstrictors). Similarly, myoactive drugs that cause bronchial smooth muscle relaxation result in bronchodilation and increased ventilation. It is also well established that myoactive drugs (causing muscle contraction or muscle relaxation) and neuroactive drugs (causing neural excitation or neural inhibition) may be used to relieve asthma (sympathomimetic bronchodilators).
Like drugs, certain gases and vapors are physiologically active substances. The gases carbon dioxide and nitric oxide are known to be vasoactive, myoactive, and neuroactive [1]. Oxygen, nitrous oxide, helium, and dilute mixtures of nitric oxide may also be vasoactive, myoactive, and/or neuroactive. In addition, vapors from certain substances that lower the pH of mucosa to a degree similar to that of carbon dioxide, such as hydrochloric acid (HCl), nitric acid (HNO3), and hydrofluoric acid (HF) (all usually diluted with air) can be effective [6], and thus, in general, isocapnic mixtures of acid gases may be effective as well. Therefore, as used herein, “gas” and “gaseous” may refer to any physiologically active gas or vapor.
If a drug is co-applied to a particular tissue or organ with CO2, NO, or other vasoactive, myoactive, or neuroactive gas or vapor as taught and claimed herein, the speed and efficacy of the drug action in such tissue or organ may be controlled. As a specific example for CO2, in an in vivo test, the ability of the drug atropine to inhibit serotonin-induced bronchial smooth muscle contraction was found to be potentiated from 46% inhibition to 62% inhibition by co-application of a 10% CO2 concentration [2]. Similarly, the inhibitory effect of the drug hexamethonium was potentiated from 37% inhibition to 67% inhibition by co-application of a 10% CO2 [2].
The co-application of a drug with a gas or vapor can be performed in at least three different ways: First, the drug and gas can be applied together locally by co-infusion and transmucosal co-absorption nasally, orally, and/or via the eye or ear. The form of the drug, of course, would need to be suitable for such infusion, for example, a fine powder or liquid. If the combination of the drug and gas is applied nasally or orally for local transmucosal absorption, the individual would substantially inhibit passage of the drug and gas into his lungs and trachea by limiting inhalation of the gas and drug. Second, the drug and gas may be applied separately. The drug may be applied by any conventional means such as inhalation, pills, capsules, hypodermic injection or epidermal patches, and the individual may infuse a nostril or nostrils, mouth, eye or ear with the gas before, during or after application of the drug. As a variation of this method of co-application, the gas may instead be inhaled. Third, a combination of the drug and gas may be inhaled.
As an example of the first method, a drug presently infused into the respiratory passages, mouth, eyes, or ears by entraining with air, e.g., as an aerosol, powder, or spray, can be applied instead by entraining with CO2, e.g., through aspiration of a drug-containing liquid or powder by CO2. In particular, the action of drugs developed and presently used for relieving respiratory and headache symptoms may be improved by their co-infusion with CO2 or NO. The vasodilation induced by CO2 or NO improves the speed and extent of absorption and distribution of the drug in the tissue in which it is co-absorbed with CO2 or NO. This is beneficial through more rapid relief being obtained, and through reduction in the quantity of drug required to obtain the relief. Reduction in the required quantity of drug reduces the cost of treatment per dose and particularly reduces the side effects of such drugs, which are severe restrictions to their present use.
With respect to the second method, a particular benefit of co-application of such drugs with CO2 is that, in addition to the reduction of the total amount of drug required, the effect of the drug can be controlled or “modulated” in the course of its action after application. Inhalation or infusion of CO2 prior to drug application can increase the effectiveness and reduce the required quantity of the drug. Alternatively, inhalation or infusion of CO2 after application of a drug can enhance the effect of the drug at a controlled rate; i.e., if a more rapid or more intense effect of the drug is desired, CO2 can be inhaled or infused at the rate required to obtain the desired degree of enhancement. A particular advantage of such control is that the drug enhancement effect can be abruptly terminated, by ceasing CO2 inhalation or infusion, at the optimum level of beneficial drug effect that minimizes side or overdose effects. Also, since CO2 is rapidly eliminated from the body via the bloodstream and respiration, the enhancement is reversible after CO2 application is ceased, allowing continuous chronic adjustment of the drug effect.
An example of the beneficial regulation of the effect of a powerful drug by CO2 inhalation or infusion is the co-application of CO2 and nitroglycerin for the relief of acute angina and during onset of a heart attack (myocardial infarction). Nitroglycerin is a powerful vasodilator. Ordinarily persons suffering from angina or from symptoms of heart attack place a nitroglycerin tablet under their tongue (transmucosal delivery). If this is not adequate to relieve the symptoms within three minutes, another tablet is similarly ingested. After another three minutes, if relief is not obtained, this process is again repeated. If the symptoms then persist, a person should be taken immediately to a hospital for emergency treatment. Some persons are extremely sensitive to the side effects of nitroglycerin however, including severe blood pressure reduction that can result in dizziness and fainting, especially after ingesting the second tablet, at a time when good judgment and deliberate corrective action are required. A few minutes of delay can be crucial after the onset of a heart attack. With co-application, CO2 can be inhaled or infused after the first tablet to rapidly enhance and sustain its effects, possibly reducing the need for subsequent tablets. The effects of a second tablet of nitroglycerin can be initiated gradually and reversibly with CO2 application to maintain and extend the optimum degree of pain relief without severe blood pressure reduction.
In all three methods cited only one physiologically active gas is used; however, physiologically active gases may be used together, with or without drugs. For example, CO2 has been found to relax both central and peripheral airways in asthmatic adults [3]. Similarly, in both in vivo and clinical tests, inhaled low dose NO has been found to be as effective as sodium nitroprusside and prostacyclin in reducing transpulmonary gradient and pulmonary vascular resistance, and is highly pulmonary vasoselective [6]. NO has also been found to reverse pulmonary hypertension [4,5]. Therefore, NO and CO2 can be co-applied to potentiate their respective actions.
An essential aspect of co-application if control of drug effect is desired is that the CO2, or similar physiologically active gaseous agent must be available for use by the affected person immediately and conveniently at the time the symptoms appear. The hand-held portable dispenser described in U.S. patent application Ser. No. 09/614,389 fulfills this requirement, but does not provide for a high flow rate which may be advantageous when co-application, and particularly inhalation, of a drug and gaseous agent are desired for potentiation. Additionally, the device described in U.S. patent application Ser. No. 09/614,389 does not provide for simultaneously administering the gaseous agent and the drug.
It is therefore an object of the invention to provide a dispenser that allows a flow rate more suitable for co-application of a drug and gaseous physiologically active agent in certain circumstances. It is a further object of the invention to provide a dispenser that allows for simultaneous co-application of a drug and gaseous physiologic agent and adjustment of the dose of the drug relative to the amount of gaseous agent administered. It is a further object of the invention to provide a method for controlling the effect of a drug through the co-application of a physiologically active agent in gaseous or vaporous form.
2. Description of Background Art
Inhalation devices, systems and methods for delivering carbon dioxide and other gases and aerosols to patients, with and without co-delivery of a drug are described in U.S. Pat. Nos. 3,776,227; 3,513,843; 3,974,830; 4,137,914; 4,554,916; 5,262,180; 5,485,827; and 5,570,683. In general, the methods and devices that provide for co-delivery of a drug and carbon dioxide or other gases do not do so for the purpose of potentiation. For example, carbon dioxide may be used simply as a safe propellant as shown in Wetterlin, U.S. Pat. No. 4,137,914. Additionally, in the devices shown, the gas and the drug are usually combined and stored together, which does not allow for adjustment of the amount of gas infused into the body. Such devices are therefore inappropriate for the purpose of controlling the drug's effect by means of the gas.
Additional background art may be found in the following references:    [1] Guyton A C, Hall J E. Textbook of Medical Physiology. Ninth Ed., W.B. Saunders Co., Philadelphia, 1996.    [2] Tang A, Rayner M, Nadel J. “Effect of CO2 on serotonin-induced contraction of isolated smooth muscle. Clin Research 20:243, 1972.    [3] Qi S, Yang Z, He B. An experiment study of reversed pulmonary hypertension with inhaled nitric oxide on smoke inhalation injury. Chung Hua Wai Ko Tsa Chih 35(1):56–8, January 1997.    [4] Loh E, Lankford E B, Polidori D J, Doering-Lubit E B, Hanson C W, Acker M A. Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy. Ann Thorac Surg 67(5):1380–5, May 1999.    [5] Pagano D, Townend J N, Horton R, Smith C, Clutton-Brock T, Bonser R S. A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation. Eur J Cardiothorac Surg 10(12):1120–6, 1996.    [6] Sterling G, et al. Effect of CO2 and pH on bronchoconstriction caused by serotonin vs. acetylcholine. J. of Appl. Physiology, vol. 22, 1972.